Composition for Inhalation

ABSTRACT

The invention relates to a formulation comprising formoterol and budesonide for use in the treatment of respiratory diseases. The composition further contains HFA 227, PVP and PEG, preferably PVP K25 and PEG 1000.

TECHNICAL FIELD

The present invention relates to a formulation comprising formoterol andbudesonide for use in the treatment of inflammatoryconditions/disorders, especially respiratory diseases such as asthma,COPD and rhinitis.

BACKGROUND

Stability is one of the most important factors which determines whethera compound or a mixture of compounds can be developed into atherapeutically useful pharmaceutical product.

Combinations of formoterol and budesonide are known in the art, see forexample WO 93/11773 discloses such a combination that is now marketed asSymbicort® in a dry powder inhaler. There are a variety of otherinhalers by which a respiratory product can be administered, such aspressurised metered dose inhalers (pMDI's). Formulations for pMDI's mayrequire certain excipients as disclosed in WO 93/05765.

It has now been found that certain HFA formulations comprisingformoterol and budesonide together with polyvinylpyrrolidone (PVP) andpolyethylene glycol (PEG) exhibit excellent physical suspensionstability.

DESCRIPTION

In accordance with the present invention, there is provided apharmaceutical composition comprising formoterol, budesonide, HFA 227(1,1,1,2,3,3,3-heptafluoropropane), PVP and PEG characterised in thatthe PVP is present from about 0.0005 to about 0.03% w/w and the PEG ispresent from about 0.05 to about 0.35% w/w.

Preferably the PVP is present in an amount of 0.001% w/w. Preferably thePVP is PVP K25 (PVP having a nominal K-value of 25).

Preferably the PEG is present in an amount of 0.3% w/w. Preferably thePEG is PEG 1000 (PEG having an average molecular weight of 1000Daltons).

Preferably the concentrations of formoterol/budesonide are such that theformulation delivers formoterol/budesonide at 4.5/40 mcg, 4.5/80 mcg,4.5/160 mcg or 4.5/320 mcg per actuation.

The formoterol can be in the form of a mixture of enantiomers.Preferably the formoterol is in the form of a single enantiomer,preferably the R, R enantiomer. The formoterol can be in the form of thefree base, salt or solvate, or a solvate of a salt, preferably theformoterol is in the form of its fumarate dihydrate salt. Other suitablephysiologically salts that can be used include chloride, bromide,sulphate, phosphate, maleate, tartrate, citrate, benzoate,4-methoxybenzoate, 2- or 4-hydroxybenzoate, 4-chlorobenzoate,p-toluenesulphonate, benzenesulphonate, ascorbate, acetate, succinate,lactate, glutarate, gluconate, tricaballate,hydroxynapaphthalenecarboxylate or oleate.

Preferably the second active ingredient is budesonide, includingepimers, esters, salts and solvates thereof. More preferably the secondactive ingredient is budesonide or an epimer thereof, such as the22R-epimer of budesonide.

The pharmaceutical compositions according to the invention can be usedfor the treatment or prophylaxis of a respiratory disorder, inparticular the treatment or prophylaxis of asthma, rhinitis or COPD.

In a further aspect the invention provides a method of treating arespiratory disorder, in particular asthma, rhinitis or COPD, in amammal, which comprises administering to a patient a pharmaceuticalcomposition as herein defined.

The compositions of the invention can be inhaled from any suitable MDIdevice. Doses will be dependent on the severity of the disease and thetype of patient, but are preferably 4.5/80 mcg or 4.5/160 mcg peractuation as defined above.

The concentration of PVP (0.001% w/w) used in this formulation has beenfound to give consistently stable formulations over the required doserange, incorporating a wide range of concentrations of the activecomponents, and at a much lower concentration than indicated in theprior art.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic drawing of an Optical Suspension Characterisation(OSCAR) set-up.

FIGS. 2-3 are graphs showing the averages of OSCAR data (lower sensor)for formulations in HFA 227 containing 4.5 μg formoterol; 0.3% w/w PEG1000; 0.0001%-0.05% w/w PVP K25; and 160 μg budesonide (FIG. 2) or 80 μgbudesonide (FIG. 3).

FIGS. 4-6 are graphs showing the averages of Turbiscan data forformulations in HFA 227 containing 4.5 μg formoterol; 0.3% w/w PEG 1000;0.0001%-0.05% w/w PVP K25; and 160 μg budesonide (FIG. 4), 80 μgbudesonide (FIG. 5), or 40 μg budesonide (FIG. 6).

FIG. 7 is a graph showing the effect of PEG 1000 concentration on stemreturn force for formulations containing 4.5 μg formoterol; 160 μgbudesonide; and 0.1%, 0.3%, or 0.5% w/w PEG 1000.

FIG. 8 is a graph showing the averages of Turbiscan data forformulations in HFA 227 containing 80 μg budesonide; 4.5 μg formoterol;0.0001% PVP K25; and 0.005%-0.5% w/w PEG 1000.

FIGS. 9-11 are a series of digital photographs, taken after standingtimes of 0 seconds (FIG. 9), 30 seconds (FIG. 10), and 60 seconds (FIG.11), of suspensions in HFA 227 containing budesonide (160 μg/actuation);formoterol (4.5 μg/actuation); 0.3% PEG 1000; and PVP K25 at 0.0001%,0.0005%, 0.001%, 0.01%, 0.03%, and 0.05% w/w.

FIGS. 12-14 are a series of digital photographs, taken after standingtimes of 0 seconds (FIG. 12), 30 seconds (FIG. 13), and 60 seconds (FIG.14), of suspensions in HFA 227 containing budesonide (80 μg/actuation);formoterol (4.5 μg/actuation); 0.3% PEG 1000; and PVP K25 at 0.0001%,0.0005%, 0.001%, 0.01%, 0.03%, and 0.05% w/w.

FIGS. 15-16 are digital photographs, taken after standing times of 0minutes (FIG. 15) and 10 minutes (FIG. 16), of suspensions in HFA 227containing budesonide (80 μg/actuation); formoterol (4.5 μg/actuation);0.001% PVP K25; and PEG 1000 at 0.005, 0.05, 0.35, and 0.5% w/w.

The invention is illustrated by the following examples.

EXPERIMENTAL SECTION

Two methods can be used to evaluate physical suspension stability:Optical suspension characterisation (OSCAR), and TURBISCAN. Both methodsare used to semi-quantify sedimentation/creaming rates. OSCARmeasurements are performed using the PET bottles directly. For TURBISCANanalysis, the suspensions are transferred to custom designed pressurecells for measurement of light transmittance and backscattering.

Methodology OSCAR

Optical Suspension Characterisation (OSCAR) equipment is custom designedfor the rapid and reproducible semi-quantification of metered doseinhaler suspension characteristics.

The OSCAR equipment utilises changes in light transmission with time, tocharacterise a pre-agitated suspension formulation (a schematic diagramof the equipment is shown in FIG. 1). The equipment consists of a twinheaded test assembly. The head on the left side of the equipment is usedwith dilute suspensions and the right for concentrated suspensions. Theselector switch mounted between the two test heads is used to alternateconcentration choice. The output from the selected test head is directedto the equipment mounted voltage display and to the computer for datalogging. The analogue signals from photodetectors are digitised and thevalues collected in data files, these are then processed using asuitable software package. There are two equipment mounted voltagedisplays, one each for the upper and lower photodetectors. The upper andlower photodetectors are height adjustable and a position readoutdisplay is provided to indicate the set height for each test run.

The Reagecon Turbidity standards (2500-4000 NTU) are used to calibratethe sensitivity of the OSCAR equipment. In this case, the 3000 NTUturbidity calibration standard is used as a standard calibration check.However any of the turbidity standards can be used to adjust thesensitivity of the probes to a specific voltage appropriate to theformulation.

Samples for test on the OSCAR equipment are presented in PET bottlescrimped with non-metering valves.

For background information and prior art for this method refer to papersfrom Drug Delivery to the Lungs IX, 1997, Method Development of theOSCAR technique for the characterization of metered dose inhalerformulations, Authors N. Govind, P. Lambert And Drug delivery to theLungs VI, 1995, A Rapid Technique for Characterisation of the SuspensionDynamics of metered Dose Inhaler Formulations, Author, P A Jinks (3MHealthcare Ltd)

Turbiscan

Turbiscan MA 2000 is a concentrated dispersion and emulsion stabilityand instability analyser, or a vertical scan macroscopic analyser. Itconsists of a reading head moving along a flat-bottomed, 5 mlcylindrical glass cell, which takes readings of transmitted andbackscattered light every 40 μm on a maximum sample height of 80 mm. Thescan can be repeated with a programmable frequency to obtain amacroscopic fingerprint of the sample.

The reading head uses a pulsed near infrared light source(wavelength=850 nm) and two synchronous detectors:

-   -   Transmission detector: Picks up light transmitted through the        solution in the tube, at 0°    -   Backscattering detector: Receives the light back scattered by        the product at 135°.

The profile obtained characterises the samples homogeneity,concentration and mean particle diameter. It allows for quantificationof the physical processes the sample is undergoing. As well as detectingdestabilisation, Turbiscan allows comparison of, for example, thesedimentation rate of different suspensions.

Turbiscan may be used in several modes, e.g., transmitted orbackscattering modes. Turbiscan has been used here in these examples tomeasure the transmitted light as a function of time.

Dispersion instability is the result of two physical processes: a)particle size increases as a result of the formation of aggregates, dueto flocculation; and b) particle migration resulting in creaming orsedimentation. When a product is stable (i.e., no flocculation, creamingor sedimentation), the transmitted and backscattered light will remainconstant i.e. scans of these will show a constant level profile. If theproduct undergoes changes in particle size, variations in thetransmitted/backscattered light show as change in the direction of thescan from horizontal or steady state profile.

For pressurised systems a cell capable of handling pressurised samplesis required. Such a cell was used for the evaluations of these HFAformulations. The scans were performed in the AUTO mode.

The % transmission averages shown in the figure (see later) were takenfrom a zone around the middle of the suspension sample.

Initial Evaluation

For the initial evaluation, only OSCAR was used.

Formulations containing formoterol fumarate dihydrate, budesonide,0.001% w/w PVP K25 and either 0.1% w/w or 0.3% PEG 1000 in HFA-227 wereprepared in polyethylene terephthalate (PET) bottles crimped with acontinuous valve. For all formulations, the formoterol fumaratedihydrate concentration remained constant at 0.09 mg/ml (equivalent to4.5 mcg formoterol fumarate dihydrate per actuation) and the budesonideconcentration varied between approximately 1 mg/ml to 8 mg/ml(equivalent to 40 mcg to 320 mcg per actuation).

Early OSCAR data for Symbicort pMDI formulations Transmittance (mV)Budesonide Formoterol PVP K25 Lower sensor dose dose concentration TimePEG concn % w/w ex-actuator ex-actuator (% w/w) seconds 0.1 0.3  40 μg4.5 μg 0.001 30 seconds 257 60 seconds 264  80 μg 4.5 μg 0.001 30seconds 202 60 seconds 240 0.002 30 seconds 184 60 seconds 185 160 μg4.5 μg 0.001 30 seconds 208 114 60 seconds 304 191 0.002 30 seconds 24860 seconds 327 320 μg 4.5 μg 0.001 30 seconds 475 60 seconds 570 0.00230 seconds 930 60 seconds 1443

OSCAR analysis of these formulations gave relatively low lighttransmittance values at the lower sensor, which is indicative of stablesuspensions with low flocculation characteristics. Early indicationswere that the 0.001% w/w PVP with 0.3% PEG 1000 would give the bestsuspension.

FURTHER EVALUATION: various concentrations of PVP K25 with a constantPEG 1000 concentration of 0.3% w/w.

OSCAR, Turbiscan and photographic methods were used to evaluate theformulations. OSCAR and Turbiscan techniques have been describedearlier. Samples with varying concentrations of PVP were analysed todetermine suspension stability over time.

Photographic Analysis

For the photographic analysis, samples were prepared in PET bottles andphotographed digitally over time, using a black background. Thesephotographs (some of which are shown here) show the behaviour of thesuspension over time and allow easy comparison of the effectiveness ofthe various concentrations of PVP. The concentration of PVP varied from0.0001 to 0.05% w/w. From left to right on the photographs theconcentration of PVP is as follows:

0.0001 0.0005 0.001 0.01 0.03 0.05 far left far right

Digital Photography of Formulations Showing Degree of Dispersion OverTime

FIGS. 9, 10 and 11 show Budesonide 160 μg/shot, Formoterol 4.5 μg/shotwith various PVP K25 concentrations and 0.3% PEG 1000 at 0, 30, and 60seconds standing time.

FIGS. 12, 13 and 14 shows Budesonide 80 μg/shot, Formoterol 4.5 μg/shotwith various PVP K25 concentrations and 0.3% PEG 1000 at 0, 30, and 60seconds standing time.

Table of Degree of Dispersion of Suspensions Over Time: (all Samples)

Photographs were taken of all doses (320 μg/4.5 μg to 40 μg/4.5 μg) at0, 15, 30, 60, 90 seconds, and 2, 5 and 10 minutes. As this produced toomany photographs to reproduce here, a chart has been constructed to givea representation of the degree of dispersion over time.

If the sample was fully suspended, the sample was rated 0, i.e., at 0minutes they were fully dispersed. From there, the samples have beenrated in increments of 1-5 at 20% intervals to express the degree ofdispersion: i.e., 0 was fully suspended and 5 fully creamed. This allowssome comparison across the whole dose range and PVP concentration rangeused.

(Note concentration of Formoterol is 4.5 μg/shot in all the samples)(Samples are all fully dispersed at 0 seconds and therefore all have ascore of 0)Fully dispersed—0More than 80% dispersed, i.e., less than 20% clear liquid present 1More than 60% dispersed, i.e., less than 40% clear liquid present 2Less than 40% dispersed, i.e., more than 60% clear liquid present 3Less than 20% dispersed, i.e., more than 80% clear liquid present 4Fully creamed 5

TABLE OF DEGREE OF DISPERSION OF SUSPENSIONS OVER TIME: ALL SAMPLES Doseμg/shot Time PVP concentration (% w/w) Budesonide Sec/mins 0.0001 0.00050.001 0.01 0.03 0.05 320 15 2 1 0-1 0-1 0-1 0-1 30 3 3 2 1-2 2 2 60 4 43-4 2 3 3-4 90 4 5 5 3 5 5 2 5 5 4-5 4-5 5 5 5 5 5 5 5 5 5 10 5 5 5 5 55 160 15 3 2 0-1 0-1 2 2 30 3 2 1 1 2 2 60 5 4 1 2 4 5 90 5 5 1 2 5 5 25 5 1 2 5 5 5 5 5 2 4 5 5 10 5 5 2 4 5 5 80 15 2 1 0 0 1 1 30 3 2 1 1 22 60 4 2 1 1-2 3 3 90 5 3 1-2 1-2 4 3 2 5 3-4 1 1 5 4 5 5 4 2 2 5 5 10 55 3 3 5 5 40 15 1 1 0 0 1 2 30 2 1 1 2 2 3 60 1-2 1 1 2 2 3 90 1-2 1-21-2 2 2-3 4 2 2 2 2 3 4 5 5 3 2 2 3 4 5 10 4-5 3 2 4 5 5

Suspensions considered excellent are highlighted in bold.

It can be seen that the formulations with 0.001% w/w PVP gave the bestsuspension stability overall.

OSCAR Data (Graphs of Light Transmission Versus Time)

FIG. 2 shows the average OSCAR transmission readings (lower sensor only)for various concentrations of PVP K25. A low transmission readingindicates that the suspension is dispersed, preventing light beingtransmitted. Hence, it can be seen that the lowest line is the moststable formulation. This is the 0.001% PVP sample.

In FIG. 3, the bottom line, again with low transmission readings,clearly shows that the formulation containing 0.001% PVP is the moststable.

Turbiscan Data (Graphs of Percentage (%) Light Transmission Versus Time)

Data from the Turbiscan can be interpreted in a similar vein to theOSCAR data in that a low percentage (%) transmission indicates thesuspension is dispersed. The % transmission averages quoted here weretaken from a zone around the middle of the suspension sample. In FIG. 4the most stable formulation is the lowest line with the lowest %transmission, i.e. the bold black line with 0.001% w/w PVP

FIGS. 5 and 6 show that the suspension with 0.001% w/w PVP is the moststable (bottom bold line) with the lowest % transmission.

Further Evaluation:

Determination of the optimum PEG 1000 concentration.

For this evaluation, photography, turbiscan and force to fire data(valve performance) was used to determine the optimum PEG concentration.

Methodology—Force to Fire (Return Force at 0.5 mm Stem Return)

Force to fire testing was performed using the Lloyd LRX testing machine.The pMDI unit to be tested was placed valve down in a can holder on thelower platform of the unit. The upper crosshead was then moved to justabove the base of the can. Can actuations were performed using astandard protocol. During measurement, force data is captured by meansof the load cell located at the top of the upper crosshead. This programwas designed to output the return force at 0.5 mm stem return as this isthe point at which the metering chamber is considered to refill.

A low return force is indicative of high friction and potential stickingproblems. It also suggests there may be a problem with low actuationweights as the propellant enters the metering chamber more slowly andhas time to vaporise. Force to fire testing was performed at presetactuations.

Data Force to Fire Data

FIG. 7 shows the effect of PEG 1000 concentration on stem return forcefor the 4.5/160 μg formoterol/budesonide formulation

This shows that at 120 actuations, the return force is greater for the0.3% w/w PEG 1000 concentration than for the other concentrations of0.5% and 0.1%. In general, the higher the return force the lesser thechance of the valve stem sticking. The above data shows that in thiscase 0.3% would be preferred.

Turbiscan Data

The Turbiscan data (FIG. 8) shows that there is little differencebetween the stability of suspensions made with varying levels of PEG1000 except for the 0.005% w/w level which was unsatisfactory.

Photographic Analysis

Digital photographs of suspensions containing Budesonide, Formoterol,HFA 227, 0.001% w/w PVP and varying levels of PEG 1000 show littlevariation in suspension stability over time (0 seconds to 10 minutes)except for the 0.005% w/w PEG level (in agreement with the Turbiscandata).

FIGS. 15 and 16 show Budesonide 80 μg/shot, Formoterol 4.5 μg/shot with0.001% PVP K25 and various concentrations of PEG 1000 at 0 (1) and 10minutes (2) standing time.

Product Performance Data

In addition to the above, product performance data for formulationscontaining formoterol fumarate dihydrate/budesonide at the followingstrengths: 4.5/80 mcg per actuation and 4.5/160 mcg per actuation, with0.001% PVP K25 and either 0.1% or 0.3% PEG 1000, were stable for up to12 months at 25° C./60% RH.

Product performance data for Symbicort formulations containing 0.001%PVP K25 and 0.1% PEG 1000 in HFA-227 Fine particle fraction (%cumulative undersize for 4.7 μm cut-off) Product strength 25° C./ 25°C./ (μg) (FFD/ 60% RH 60% RH budesonide) Drug Initial 6 months 12 months4.5/80 Budesonide 51.3 52.8 62.0 FFD 55.4 53.5 59.7 4.5/160 Budesonide50.0 48.8 47.0 FFD 54.2 52.1 51.3

Product performance data for Symbicort formulations containing 0.001%PVP K25 and 0.3% PEG 1000 in HFA-227 Fine particle fraction (%cumulative undersize for 4.7 μm cut-off) Product strength 25° C./ 25°C./ (μg) (FFD/ 60% RH 60% RH budesonide) Drug Initial 6 months 12 months4.5/80 Budesonide 55.8 50.6 51.3 FFD 64.2 57.6 58.7 4.5/160 Budesonide48.7 50.2 52.3 FFD 55.6 59.1 61.2

1. A pharmaceutical composition suitable for administration to a patientcomprising formoterol, budesonide or an epimer thereof,1,1,1-2,3,3,3-heptafluoropropane (HFA 227), polyvinyl pyrrolidone (PVP),and polyethylene glycol (PEG).
 2. A pharmaceutical composition accordingto claim 1 wherein the PVP is present from about 0.0001 to about 0.05%w/w and the PEG is present from about 0.05 to about 0.35% w/w.
 3. Apharmaceutical composition according to claim 1 in which the PVP is PVPK25.
 4. A pharmaceutical composition according to claim 1 in which thePVP is present in an amount of 0.001% w/w.
 5. A pharmaceuticalcomposition according to claim 1 in which the PEG is PEG
 1000. 6. Apharmaceutical composition according to claim 1 in which the PEG ispresent in an amount of 0.3% w/w.
 7. A pharmaceutical compositionaccording to claim 1 in which formoterol is in the form of its fumaratedihydrate salt.
 8. A pharmaceutical composition according to claim 1 inwhich the formoterol is in the form of the single R,R-enantiomer.
 9. Apharmaceutical composition according to claim 1 in which the secondactive ingredient is the 22R-epimer of budesonide.
 10. (canceled) 11.(canceled)
 12. (canceled)
 13. The pharmaceutical composition accordingto claim 1, wherein the pharmaceutical composition is in the form of asuspension.